Excipient changes studies

Minimally, one should have a brief foreknowledge of the thermal and thermal/humidity solid-state stability of the API prior to initiation of excipient compatibility studies. These protocols should include investigation of stability at various temperature and humidity conditions and should always include information about both chemical stability and physical-form integrity of the API. Thermal and thermal moisture-induced solid-state chemical reactions are well known (5), with hydrolysis and oxidation being the most prevalent mechanisms of decay. Changes in physical form with thermal and... 

In the process of stressing API in the presence of excipients, one should take into account the potential for physical change of the API to occur in the formulation mixtures being evaluated. Depending on the stage of development and the depth of excipient compatibility studies, physical form assessment may be cursory or more extensive, but should be considered at some level. 

Kinetic information on the chemical changes of excipient compatibility samples is a direct outcome of most formulation compatibility studies. Because accelerated conditions of thermal and thermal humidity stress are employed, degradation will often occur at these conditions. A brief kinetic evaluation of the data can address the behavior and extent of decay such that degradation data can effectively be utilized to determine levels and conditions of compatibility (96). It is not the aim of this section to recommend full kinetic treatment of decay rather it is to describe simple concepts and exercises that will help the excipient compatibility formulator utilize their data most effectively. Several experimental factors can be included in the initial experimental design of excipient compatibility studies to make kinetic analysis more powerful, and even with small studies having a limited amount of samples for analysis, a brief kinetic treatment of the data is recommended. 

Prestrelski et al. [3.58] studied the pH conditions and different stabilizers to provide optimum storage stability for IL-2 by Fourier transform IR spectroscopy. Different pH conditions in the absence of excipients change the dry state conformation of... 

Nonclinical (Pharmtox, PK, PD) In the context of FOPs, the original sponsor will have demonstrated what the molecule per se does to the body however, since the formulation is likely different, nonclinical studies are useful in demonstrating a lack of adverse impact due to dosage form, route of administration, excipient changes, manufacturing contaminants, and supporting sameness of the active moiety. 

With justification, bracketing can be applied to studies with multiple strengths where the relative amounts of drug substance and excipients change in a formulation. Such justification can include a demonstration of comparable stability profiles among the different strengths of clinical or development batches. 

Other workers have used the tristimulus parameters to study the kinetics of decomposition reactions. The fading of tablet colorants was shown to follow first-order reaction kinetics, with the source of the illumination energy apparently not affecting the kinetics [49]. The effect of excipients on the discoloration of ascorbic acid in tablet formulations has also been followed through determination of color changes [50]. In this latter work, it was established that lactose and Emdex influenced color changes less than did sorbitol. 

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